Abstract Mitochondrialdysfunctionresultsindisordersthataffectonein4,000people,anddiseasesassociated withaging,suchasneurodegenerationandcancer.Improperfunctionofamitochondrialqualitycontrol process,mitophagy,aswellasmutationsinmitochondrialDNA(mtDNA)areimplicatedinthese diseases.TheroleofenvironmentalpollutantsandmitophagyintheoriginandtransmissionofmtDNA mutationsispoorlyunderstood.Theobjectiveofthisproposalistoinvestigatevariationinsusceptibility tochemical-inducedmtDNAdamageinthecontextofmitochondrialhomeostaticprocesses,howDNA damagecanleadtomtDNAmutations,andthefunctionalconsequencesofthesemutations.Themodel organismCaenorhabditiseleganshasahighlyconservedmitochondrialgenomeandwellcharacterized mitochondrialbiology,andprovidesanextremelytractablegeneticandtoxicologicalmodelforthis researchproposal.WehypothesizethatC.elegansthataregeneticallydeficientinmitophagywill accumulateandretainhigherlevelsofmtDNAdamagecomparedtowildtypeafterexposuretothe environmentaltoxicantsandknownmutagens,cadmiumandAflatoxinB1.Weproposethatthiswill increasemtDNAmutationfrequencies.Thisworkwillalsoinformtheroleofmitophagyintransmission ofmtDNAmutationsintothenextgeneration.TodetectraremtDNAmutations,wewilladaptawell- establishedandhighly-sensitivesequencingplatform,DuplexSequencing,forC.elegansforthefirst time.Thiswillfulfillasignificantgoalofthetrainingplan,whichistobecomeproficientincomputational biologyandbioinformatics.Wewillalsoinvestigatethepotentialhealtheffectsontheorganism, includingmitochondrialfunction,reproduction,andlifespanasaconsequenceofmtDNAmutations. Overall,thisresearchisimpactfulbecauseitwillprovidebetterunderstandingoftherolethatexposures toenvironmentalpollutantsandgeneticsusceptibilityplayintheorigin,signature,transmission,and effectsofmtDNAmutations.